Methyl-alkyl ketones, aldol reactions

Kuwajima and coworkers used very hindered bases such as (2) to deprotonate methyl alkyl ketones regioselectively in the presence of enolizahle aldehydes.One example of this amazing process is shown in equation (11) the reaction is reported to work equally well with other methyl ketones, including 2-pentanone. The process was also demonstrated with other bases in the reaction of 3-methyl-2-buta-none with dihydrocinnamaldehyde (equation 12). Among the bases that are effective are LDA, lithium hexamethyidisilazane, lithium r-butoxide and even lithium ethoxide. However, base (2) is superior, giving the aldol in 83% yield. 

High electrophilic ketones, such as compounds 85 reacted with acetone (3a) using very bulky sulfonamide 79e in combination with trifluoroacetic acid (10 mol%) as catalysts (Scheme 4.27). Also different methyl alkyl ketones could be used with similar results, taking part the reaction always at the methyl group. The absolute configuration of final aldol was determined in basis of crystallographic determinations [153]. 

TABLE 3.2. Asymmetric Aldol Reaction of Methyl-Alkyl Ketones [58]... 

The kinetic diethylaluminium enolates (100), prepared from ketones, react regioselectively in a crossed-aldol reaction with carbonyl compounds in high yield [equation (61)]. Similarly, the di-isobutylaluminium kinetic enolates (101) are implicated in the regioselective self-condensation of methyl alkyl ketones (Scheme 74). ... 

Trimethylphenoxymagnesium bromide also generates the corresponding kinetic enolate of methyl alkyl ketones and effects the regioselective crossed-aldol reaction with a,/8-unsaturated aldehydes in moderate yields. ... 

The ketone 73 was reduced chemo- and diastereoselectively and protected to provide the silyl ether 74. The ester function was then deprotonated to the corresponding ester enolate (75) that was alkylated with methyl iodide exclusively from the Re face of the enolate to afford the bicycle 76 (Scheme 11). The substrate for the retro-aldol reaction (77) was prepared by a sequence that consists of seven functional and protecting group transformations. The retro-aldol reaction converted the bicyclic yS-hydroxy ketone 77 into the 1,3-diketone 69 via the alkoxide (78) in very good yield. 

A total synthesis of ( )-aromatin has utilized the lithium anion of the dithiane of (E)-2-methyl-2-butenal as a functional equivalent of the thermodynamic enolate of methyl ethyl ketone in an aprotic Michael addition (Scheme 189) (81JOC825). Reaction of the lithium anion (805) with 2-methyl-2-cyclopentenone followed by alkylation of the ketone enolate as its copper salt with allyl bromide delivered (807). Ozonolysis afforded a tricarbonyl which cyclized with alkali to the aldol product (808). Additional steps utilizing conventional chemistry converted (808) into ( )-aromatin (809). 

If the ketone is blocked on one side so that it cannot enolize—in other words it has no a protons on that side—only one aldol reaction is possible. Ketones of this type migitt bear a tertiary alkyl or an aryl substituent, f- Butyl methyl ketone (3,3-dimethylbutan-2-one), for example, gives aldol reactions with various bases in 60-70% yield. Enolization cannot occur towards the t- butyl group and must occur towards the methyl group instead. 

Intramolecular versions of reactions other than aldols can also be considered as useful options to prepare five- or six-membered rings from their corresponding bifunctional precursors. Several examples to illustrate the diverse approaches to construct five-membered rings are given in Scheme 2.110. A high-yield method to prepare cyclopentenone 284 is given in the sequence (i) alkylation of formyl-anion equivalent 285 to give 286 (ii) Michael addition of the latter to methyl vinyl ketone (iii) removal of the carbonyl protection and (iv) intramolecular cyclization of the 1,4-diketone, 287. 

The Evans asymmetric alkylation [127] and aldol reactions were also effectively applied to the synthesis of the C10-C19 top segment 230 (Scheme 33). The starting chiral unit 223 was synthesized via the Evans asymmetric alkylation of 218a. The subsequent Evans aldol reaction of 223 with 224 followed by trans-amidation yielded 2,3-sy -diol derivative 225 with complete stereoselectivity. Addition of alkyl lithium 226 to the Weinreb amide 225 produced ketone 227, which was stereoselectively reduced and methylated to give dimethyl ether 228. The standard functional group manipulation afforded thioacetal 229, which was converted into phosphine oxide 230. 

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